3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity.

Zheng, Yang; Müller, Joachim; Kunz, Stefan; Siderius, Marco; Maes, Louis; Caljon, Guy; Müller, Norbert; Hemphill, Andrew; Sterk, Geert Jan; Leurs, Rob (2022). 3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity. International journal for parasitology. Drugs and drug resistance, 19, pp. 47-55. Elsevier 10.1016/j.ijpddr.2022.05.004

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As there is a continuous need for novel anti-infectives, the present study aimed to fuse two modes of action into a novel 3-nitroimidazo[1,2-b]pyridazine scaffold to improve antiparasitic efficacy. For this purpose, we combined known structural elements of phosphodiesterase inhibitors, a target recently proposed for Trypanosoma brucei and Giardia lamblia, with a nitroimidazole scaffold to generate nitrosative stress. The compounds were evaluated in vitro against a panel of protozoal parasites, namely Giardia lamblia, Trypanosoma brucei, T. cruzi, Leishmania infantum and Plasmodium falciparum and for cytotoxicity on MRC-5 cells. Interestingly, selective sub-nanomolar activity was obtained against G. lamblia, and by testing several analogues with and without the nitro group, it was shown that the presence of a nitro group, but not PDE inhibition, is responsible for the low IC50 values of these novel compounds. Adding the favourable drug-like properties (low molecular weight, cLogP (1.2-4.1) and low polar surface area), the key compounds from the 3-nitroimidazo[1,2-b]pyridazine series can be considered as valuable hits for further anti-giardiasis drug exploration and development.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology

UniBE Contributor:

Müller, Joachim; Müller, Norbert and Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture

ISSN:

2211-3207

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

22 Jun 2022 15:07

Last Modified:

22 Jun 2022 15:15

Publisher DOI:

10.1016/j.ijpddr.2022.05.004

PubMed ID:

35716585

Uncontrolled Keywords:

3-nitroimidazo[1,2-b]pyridazine 3′,5′-cyclic nucleotide phosphodiesterase Giardia lamblia In vitro Synthesis

BORIS DOI:

10.48350/170829

URI:

https://boris.unibe.ch/id/eprint/170829

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